Targeting proteins to ideally restore normal biological processes is a common starting point in drug discovery ¹ . The Open PHACTS Discovery Platform (OPDP) was designed to help identify protein targets and information about their associations with each other ^{2– 4} . The OPDP supports target identification and validation by including target-target interactions from WikiPathways ^{5– 7} . Of these interaction networks, proteins sharing a downstream path allows investigation of alternative drug target combinations. Even the knowledge of which biological pathways participate in disease-related processes provides insight in the pathway topology between the targets. The importance and need of providing access to interaction information for real-world research questions was outlined in a recent Open PHACTS paper ⁸ .

The Open PHACTS project was born out of the desire to integrate pharmacological data from multiple pre-competitive sources to efficiently address scientific questions that cannot be answered with single data sources ⁸ . It integrates data using linked data approaches ³ from chemical and biological sources such as ChEBI, ChEMBL, UniProt, and WikiPathways ⁶ . However, the OPDP did not previously include calls to access specific up- and downstream interaction effects. This information is needed for questions related to drug repositioning and repurposing. Up- or downstream targets may be interesting alternatives with similar therapeutic effect to targets, for which it is particularly hard to develop an drug agent. Thus, finding a target that has already been drugged or is more drug tractable will be advantageous. Here we describe how to identify alternative targets in the same cellular pathway using OPDP against the WikiPathways data.

We are demonstrating the platform with three example calls. All the API calls require use of an application ID and an application key. This key and ID can be acquired by creating a free Open PHACTS account. The first example is an application to the PI3K/AKT pathway for cell growth regulation which contain important targets for cancer treatment ¹³ . The AKT protein has a central role and usefully shows the API call’s ability to return connected elements with the first and third calls. The API call can help aid drug discovery by taking a target, in this case AKT, and easily identify other connected proteins that could potentially be used as drug targets with a common downstream effect.

Figure 1 shows the web interface of the API call that returns the connectivity of the AKT2 target to both upstream or downstream proteins or gene products. This method allows the user to identify connections to other targets in the pathway. The results of that API call ( Figure 2) show the AKT2 interaction with microRNA. A helper method ( Figure 3): /pathways/interactions/byEntity/count is also included. It returns the number of all interactions in which an entity is participates. This helps the user get a sense of the prevalence of the queried entity with interactions in pathways found on WikiPathways.

The other call implemented, /pathway/getInteractions ( Figure 4), demonstrates an API call to return all interactions in the MicroRNAs in cardiomyocyte hypertrophy pathway ¹⁴ . This pathway has interaction details for AKT, mTOR, and PI3K, which are all important targets in cancer research ¹⁵ . For each interaction the participants are given and whether it is a directed or undirected interaction.

The addition of interactions with direction information allows OPDP to answering more of the pre-defined scientific questions ¹⁶ . The directional information allows the user to explore how proteins and gene products are connected with one another and easily access this information. This is illustrated in the example queries using the cancer target AKT.

Online service: https://dev.openphacts.org/docs/2.1

Latest source code is available at: https://github.com/openphacts/OPS_LinkedDataApi

Archived source code of discussed version: https://doi.org/10.5281/zenodo.1068252 ¹⁷

License: Apache License 2.0